Exendin-4 gene modification and microscaffold encapsulation promote self-persistence and antidiabetic activity of MSCs

Yuanyuan Zhang; Shuang Gao; Kaini Liang; Zhaozhao Wu; Xiaojun Yan; Wei Liu; Junyang Li; Bingjie Wu; Yanan Du

doi:10.1126/sciadv.abi4379

Exendin-4 gene modification and microscaffold encapsulation promote self-persistence and antidiabetic activity of MSCs

Sci Adv. 2021 Jul 2;7(27):eabi4379. doi: 10.1126/sciadv.abi4379. Print 2021 Jul.

Authors

Yuanyuan Zhang¹, Shuang Gao¹, Kaini Liang¹, Zhaozhao Wu¹, Xiaojun Yan², Wei Liu², Junyang Li¹, Bingjie Wu¹, Yanan Du³

Affiliations

¹ Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
² Beijing CytoNiche Biotechnology Co. Ltd., Beijing 100195, China.
³ Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. duyanan@tsinghua.edu.cn.

Abstract

Mesenchymal stem cell (MSC)-based therapy to combat diabetic-associated metabolic disorders is hindered by impoverished cell survival and limited therapeutic effects under high glucose stress. Here, we genetically engineered MSCs with Exendin-4 (MSC-Ex-4), a glucagon-like peptide-1 (GLP-1) analog, and demonstrated their boosted cellular functions and antidiabetic efficacy in the type 2 diabetes mellitus (T2DM) mouse model. Mechanistically, MSC-Ex-4 achieved self-augmentation and improved survival under high glucose stress via autocrine activation of the GLP-1R-mediated AMPK signaling pathway. Meanwhile, MSC-Ex-4-secreted Exendin-4 suppressed senescence and apoptosis of pancreatic β cells through endocrine effects, while MSC-Ex-4-secreted bioactive factors (e.g., IGFBP2 and APOM) paracrinely augmented insulin sensitivity and decreased lipid accumulation in hepatocytes through PI3K-Akt activation. Furthermore, we encapsulated MSC-Ex-4 in 3D gelatin microscaffolds for single-dose administration to extend the therapeutic effect for 3 months. Together, our findings provide mechanistic insights into Exendin-4-mediated MSCs self-persistence and antidiabetic activity that offer more effective MSC-based therapy for T2DM.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).